A new polymorphism in the human factor VIII gene: implications for linkage analysis in haemophilia A and for the evolution of int22h sequences

Abstract

Summary.A new polymorphism in the human factor VIII gene has been localized and characterized. It is a biallelic, single nucleotide polymorphism located in intron 22 of the gene, within the 9´5 kb int22h-1 segment. The allelic forms are G (frequency 0´65) and A (frequency 0´35), giving a predicted rate of heterozygosity of 0´46. The polymorphism occurs within a CG dinucleotide and affects an MspI site (CCGG). Int22h-1 is duplicated twice extragenically at Xq28; both extragenic copies (int22h-2 and -3) are also polymorphic with respect to MspI. Investigation of 156 MspI [±] alleles, comprising 30 intragenic and 126 extragenic sites, indicated that all were due to A alleles and none had arisen by C to T transition within the CG dinucleotide. The intragenic MspI site (designated MspI A) is located 737 bases downstream of a previously described XbaI restriction fragment length polymorphism. Despite their close proximity, the polymorphisms are not in complete linkage disequilibrium; haplotype analysis in 85 factor VIII genes from a Caucasian population predicts an informativity of approximately 60% in linkage studies using both, compared with an informativity of approximately 47% in studies using either on its own.

Combined analysis of the MspI and XbaI polymorphisms in intron 22 of the factor VIII gene for detection of hemophilia A in a Korean population

“…In addition, the MspI polymorphism of int22h-1, which is 737 bp away from the XbaI polymorphism site, had a heterozygosity rate of 49.5%, and allelic frequencies were 0.61 and 0.39, respectively, for the (+) and (-) alleles (allele +/-= 0.61/0.39 ± 0.0335, 95%CI) in this study. These results are similar to those of Bowen et al (2000), where the heterozygosity rate was 0.46, and allelic frequencies were 0.65 and 0.35, respectively, for the (+) and (-) alleles in 85 male hemophilia A patients in South Wales. This information suggested that a slightly higher informative rate was obtained in the Korean population.…”

“…The XbaI and MspI polymorphisms are located within a 9.5-kb stretch of the int22h-1 sequence. The extragenic homologous sequences, int22h2-2 and int22h-3, also have polymorphic sites for XbaI and MspI (Chan et al, 1989;Naylor et al, 1995;Bowen et al, 2000). Thus, detection of XbaI/int22h-1 and MspI/int22h-1 polymorphisms at the three polymorphic sites of int22h would require efficient amplification of those specific sequences (De Brasi et al, 1999;El-Maarri et al, 1999).…”

“…Despite their close proximity to each other, these polymorphisms are known to not be in complete linkage disequilibrium. Bowen et al (2000) reported that when 85 male residents of South Wales were studied, the informative rate increased to 60% through the combined use of MspI and XbaI polymorphisms of int22h-1. This finding, however, has not been shown to be applicable to people of other regions, especially Asian countries.…”

“…The MspI polymorphism is located 737 bases downstream from the XbaI polymorphism (Bowen et al, 2000). Despite their close proximity to each other, these polymorphisms are known to not be in complete linkage disequilibrium.…”

Carrier analysis for hemophilia A: ideal versus acceptable

“…A dimorphism within intron 22, MspA1I, has been described which is in close proximity to XbaI dimorphism but is not in complete linkage disequilibrium and may be useful in some family studies [7].…”